My Vision Test

A free modern Amsler Grid test for Macular Degeneration

MyVisionTest News Archive

Apr 22, 2009

Avastin-PDT combination therapy for AMDA new study finds that combination therapy with Avastin and photodynamic therapy (PDT) for patients with choroidal neovascularization (CNV) due to age-related macular degeneration (AMD) led to improved vision for most patients and required fewer retreatments than is usually required using monotherapy.

PDT with Visudyne (verteporfin) was the first available drug therapy for patients with subfoveal CNV caused by AMD. PDT monotherapy reduces the risk of moderate and severe vision loss in patients with wet AMD; however, it rarely results in recovery of vision. However, anti-VEGF therapy with Lucentis (ranibizumab) results in moderate vision gain in 25% to 40% of patients with wet AMD when used as monotherapy. Similar results have been reported for off-lable use of Avastin.

Verteporfin PDT and anti-VEGF therapies have different mechanisms of action, so it was hypothesized that combination therapy could result in additive or complementary effects, possibly reducing the need for frequent retreatment with one or both therapies. Verteporfin is an intravenously administered light-activated drug (photosensitizer) that targets the vascular component of CNV and halts the progression of disease by occluding the abnormal, leaking blood vessels. The drug preferentially accumulates in neovascular vessels, including CNV, and is activated by selectively applying laser light to the CNV lesion, which generates singlet oxygen and free radicals, leading to thrombosis of the vasculature and occlusion of the CNV and surrounding vessels. In contrast, anti-VEGF agents interrupt the angiogenic cascade that stimulates the growth of new blood vessels by inhibiting the action of VEGF that contributes to the development and increased permeability of CNV. This may prevent the development of new CNV, reduce the further growth of existing CNV, and decrease retinal leakage, thereby stabilizing and possibly improving vision. Unfortunately, anti-VEGF monotherapy necessitates multiple, sometimes monthly, injections with per-injection risks of endophthalmitis and retinal detachment. Even in an as-needed paradigm, frequent visits are required, creating a burden on patients, caregivers, and the health care system.

Combining verteporfin PDT with an anti-VEGF agent, two therapies that have distinctly different mechanisms of action, may result in additive or complementary effects that safely reduce the number of required treatments of both therapies while maintaining good visual results. Such combined therapy was evaluated using the Registry of Visudyne AMD Therapy.

The goal of the Registry of Visudyne AMD Therapy database was to explore the effectiveness and safety of combination treatment with Avastin delivered within 14 days of verteporfin PDT from actual clinical practice and to determine if different practice patterns or baseline demographic variables might affect outcomes. Results of the pooled analysis of patients entered into a secure online database are reported below.

This study included 1196 patients with CNV due to AMD who received at least 1 combination treatment of 1.25 mg intravitreal Avastin within 14 days of verteporfin PDT. Physicians from 45 clinical centers entered patient data at baseline and follow-up examinations, including subsequent treatments, into a secure, Web-accessed database. Snellen visual acuity (VA) was converted to logarithm of the minimum angle of resolution (logMAR) for statistical analyses.

Of 1196 patients, 1073 patients had 6 or more months of follow-up. For these 1073 patients, mean baseline VA was 0.967 logMAR (approximate Snellen 20/185) and 56.3% of patients (604/1073) were treatment naïve. After their baseline combination treatment, patients received a mean of 0.6 additional verteporfin PDT retreatments and 2.0 Avastin retreatments over a mean follow-up period of 15.0 months.

By 12 months, 82% of patients (578/701) had stable or improved vision (loss of <3 lines or a gain in VA), 36% (255/701) improved by 3 or more lines, and 17% (121/701) improved by 6 or more lines.

Patients who were treatment naive gained significantly more VA by month 12 (+8.4 letters) compared with those who had been previously treated (+2.4 letters; P<0.01).

Most serious adverse events (26/30) were judged by investigators as not related to any study treatment, although 3 ocular events were judged related to bevacizumab alone, and 1 ocular event was judged related to both bevacizumab and PDT.

The investigators conclude that combination therapy with PDT and Avastin led to vision benefit for most patients, particularly those who were treatment naive at baseline. The number of retreatments was lower than published reports with either treatment delivered as monotherapy. Randomized clinical trials are underway to confirm these findings.

Patients in the registry showed a rapid and sustained improvement in vision after combination therapy, with a mean 7.4-letter VA gain observed at 2 months and a mean 6.0-letter VA gain at 12 months. A subgroup of registry patients with baseline characteristics similar to patients enrolled in the Phase III Lucentis trials (treatment-naive patients with baseline VA of 20/50–20/500), showed that 82% had stable or improved VA and 37% had at least a 3-line gain in VA at 12 months.

Over the 15 months of follow-up, 3.2 Avastin injections and 1.6 PDT treatments, including the baseline treatment, were administered, on average. After their initial combination treatment, almost one third of patients did not receive additional treatment during follow-up.

In the absence of large, randomized, controlled studies of combination therapy, and given the limitations of the registry, especially when compared with Phase III studies (which are prospective, controlled, masked, and randomized), the registry VA outcomes are consistent with those from the Phase III Lucentis trials, and the number of retreatments in the registry was fewer than that seen for either Lucentis (for which monthly treatment was mandatory) or PDT monotherapy.

In summary, based on this large, retrospective, multicenter registry, by 12 months patients with CNV due to AMD gained a mean of approximately 1.2 lines (6.0 letters) of VA after initial combination treatment with verteporfin PDT and Avastin, regardless of subsequent retreatment. Overall, the number of retreatments was low. Treatment-naive patients responded better to combination therapy than those who had received prior treatment. No significant safety issues were apparent with combination verteporfin PDT and intravitreal Avastin therapy. Randomized clinical trials are underway to confirm these findings.

WHAT IT MEANS TO YOU: I think it is fair to say that PDT is no longer viewed as a first-line therapy for most patients with wet AMD. This is because PDT usually will not improve vision, whereas anti-VEGF therapy often will. Therefore, the new role of PDT is as a potential augmentation for anti-VEGF therapy, with the aim of decreasing the number of retreatments. Concerns still linger about the potential for secondary chorioretinal atrophy that results in vision loss following PDT. Indeed, 14% of the patients in this study underwent reduced fluence PDT, a modification of the original PDT protocol that decreases the intensity of the treatment in the hope of decreasing the risk of secondary atrophy. The need for augmentation may pass when new more powerful anti-VEGF agents, such as VEGF Trap, become available. In the meanwhile, PDT may serve a useful role in decreasing the need for retreatment in patients receiving Avastin or Lucentis.